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- PDB-8par: Crystal structure of human MAP4K1 with an inhibitor, BAY-405 -

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Basic information

Entry
Database: PDB / ID: 8par
TitleCrystal structure of human MAP4K1 with an inhibitor, BAY-405
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / kinase / inhibitor / drug discovery
Function / homology
Function and homology information


MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / cell population proliferation / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / membrane / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase kinase kinase kinase / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (CNH) domain / Citron homology (CNH) domain profile. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. ...Mitogen-activated protein (MAP) kinase kinase kinase kinase / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (CNH) domain / Citron homology (CNH) domain profile. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsSchaefer, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer.
Authors: Mowat, J. / Carretero, R. / Leder, G. / Aiguabella Font, N. / Neuhaus, R. / Berndt, S. / Gunther, J. / Friberg, A. / Schafer, M. / Briem, H. / Raschke, M. / Miyatake Ondozabal, H. / ...Authors: Mowat, J. / Carretero, R. / Leder, G. / Aiguabella Font, N. / Neuhaus, R. / Berndt, S. / Gunther, J. / Friberg, A. / Schafer, M. / Briem, H. / Raschke, M. / Miyatake Ondozabal, H. / Buchmann, B. / Boemer, U. / Kreft, B. / Hartung, I.V. / Offringa, R.
History
DepositionJun 8, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0323
Polymers34,4181
Non-polymers6152
Water84747
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint-1 kcal/mol
Surface area15160 Å2
Unit cell
Length a, b, c (Å)76.723, 100.205, 39.497
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase kinase 1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEK kinase kinase 1 / MEKKK 1


Mass: 34417.809 Da / Num. of mol.: 1 / Mutation: T165E, S171E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-XON / ~{N}-[3,5-bis(fluoranyl)-4-[[3-[1-(trifluoromethyl)cyclopropyl]-1~{H}-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]-2,9-dioxa-4-azaspiro[5.5]undec-3-en-3-amine


Mass: 522.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23F5N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.21 Å3/Da / Density % sol: 44.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.1M TRIS pH 8.0, 20 % MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2→41.95 Å / Num. obs: 20999 / % possible obs: 98.6 % / Redundancy: 7.2 % / CC1/2: 0.999 / Rrim(I) all: 0.113 / Net I/σ(I): 14.22
Reflection shellResolution: 2→2.12 Å / Redundancy: 7.1 % / Mean I/σ(I) obs: 1.29 / Num. unique obs: 3287 / CC1/2: 0.703 / Rrim(I) all: 1.694 / % possible all: 97.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→41.95 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.897 / SU B: 16.316 / SU ML: 0.203 / Cross valid method: THROUGHOUT / ESU R: 0.219 / ESU R Free: 0.199 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29244 1050 5 %RANDOM
Rwork0.23953 ---
obs0.24221 19949 98.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 56.109 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å2-0 Å2-0 Å2
2---2.41 Å20 Å2
3---3.63 Å2
Refinement stepCycle: 1 / Resolution: 2→41.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2125 0 43 47 2215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0132218
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172158
X-RAY DIFFRACTIONr_angle_refined_deg1.5191.6393004
X-RAY DIFFRACTIONr_angle_other_deg1.2081.5844977
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9545265
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.92722.286105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.23515394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.9351512
X-RAY DIFFRACTIONr_chiral_restr0.0710.2277
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022426
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02485
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5895.0031069
X-RAY DIFFRACTIONr_mcbond_other2.5884.9991068
X-RAY DIFFRACTIONr_mcangle_it4.1567.4821331
X-RAY DIFFRACTIONr_mcangle_other4.1557.4871332
X-RAY DIFFRACTIONr_scbond_it2.4385.3061149
X-RAY DIFFRACTIONr_scbond_other2.4375.3061150
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.9487.8271671
X-RAY DIFFRACTIONr_long_range_B_refined6.59857.0952493
X-RAY DIFFRACTIONr_long_range_B_other6.58357.072489
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 74 -
Rwork0.383 1415 -
obs--97.38 %
Refinement TLS params.Method: refined / Origin x: 13.9454 Å / Origin y: 12.8342 Å / Origin z: 19.0061 Å
111213212223313233
T0.0712 Å20.0074 Å20.029 Å2-0.0415 Å2-0.0111 Å2--0.064 Å2
L0.3516 °20.4801 °20.3174 °2-0.9379 °20.5284 °2--0.3189 °2
S-0.0102 Å °0.0297 Å °-0.1233 Å °0.1048 Å °0.1108 Å °-0.1278 Å °0.0344 Å °0.0495 Å °-0.1006 Å °

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